PROJECT SUMMARY: Bipolar disorder (BD) is associated with a suicide attempt rate of up to 50% and completion rate of up to 20%, making prevention and treatment of suicidal behavior in BD one of the most critical challenges that Psychiatry faces. Women with BD have much higher rate of suicide attempts (SA) than men, and completion rates are on the rise. The RDoC Suicide Task Force revealed several endophenotypes that may distinguish attempters versus non-attempters including reward responsiveness and response inhibition. Further, evidence from fMRI studies indicates that attempters and non-attempters have different brain responses to reward and inhibition tasks. Alterations have been observed in the dlPFC and OFC, and these are also the brain regions highly associated with the suicide-related endophenotypes. Unfortunately, the molecular mechanisms underlying suicidal behavior are not well elucidated and current medications are often ineffective in reducing the rates of suicide completion. In order to provide more effective treatments for the highly prevalent suicidal behavior in BD, it is necessary to elucidate the molecular mechanisms that underlie its associated features, so that they can be targeted with new treatments in men and women with BD. We have exciting new preliminary evidence supporting the involvement of cortical metabotropic glutamatergic receptors (mGluR5s) in suicidal behavior. mGluR5 aid in regulation of other glutamatergic receptors, neurotransmission and synaptic plasticity, which are all critical to healthy mood regulation and cognitive processes. Modulation of mGluR5 was shown to play a role in reward processing and impulsivity, and mGluR5 associated genes and proteins have been implicated in suicide specifically. Our novel in vivo data suggest that higher dlPFC and OFC mGluR5 availability may be a trait marker of suicidal behavior in BD and may therefore aid with the identification of patients at higher risk for completed suicide. We built upon this knowledge and developed an innovative multidisciplinary approach to studying this novel mechanism in suicidal behavior. State of the art positron emission tomography (PET) methods will be used to measure prefrontal cortical mGluR5 levels in groups of individuals with BD who have and have not attempted suicide in the past. The relationships between mGluR5 levels and suicide-related endophenotypes will be assessed. Importantly, we will examine the role of sex in the association between severity of dysregulation in mGluR5 and suicide related endophenotypes, with the hypothesis that women will exhibit a greater extent of dysregulation in mGluR5 as compared to men. Further, we hypothesize that individuals in the BD attempt group will have the greatest dysregulation in mGluR5, and that this will be associated with greatest deficits in the related endophenotypes. These results may lead to a breakthrough in determining a mechanism that may be important in the pathophysiology of suicidal behavior, and one that can be targeted for critically-needed improved detection, treatment and prevention of suicide in BD and potentially other high-risk disorders.